METASTROKE refines genetic stroke culprits

An analysis from the METASTROKE collaboration confirms an increased stroke risk associated with four previously reported genetic loci and shows that these are specific to certain stroke subtypes.

In a commentary accompanying the study in The Lancet Neurology, Philippe Amouyel (Institut Pasteur de Lille, France) points out that, because of the small proportion of strokes to which such genes contribute, the focus of wide-scale genetic studies is not in developing genetic screens for stroke risk.

"Rather, such studies are invaluable to detect underlying biological mechanisms associated with diseases and to identify new pathways," he says. "It is interesting to note that cardioembolic stroke and atrial fibrillation are associated with the same genes, and that large-vessel strokes have a susceptibility gene in common with myocardial infarction and aneurysm."

The four confirmed loci are HDAC9, PITX2, ZFHX3, and the 9p21 locus on chromosome 9. Of these, PITX2 and ZFHX3, which have previously been linked to atrial fibrillation, were associated only with cardioembolic stroke. HDAC9 and the 9p21 locus were both associated only with large-vessel stroke; the 9p21 locus has previously been linked to the risk for myocardial infarction and intracranial aneurysms.

Two other previously identified risk loci were not confirmed: NINJ2 on chromosome 12 and PRKCH. The latter locus was identified in Japanese populations, whereas all 15 cohorts included in the METASTROKE analysis were European.

The cohorts included a total of 12,389 ischemic stroke patients and 62,004 controls. Among these individuals, Hugh Markus (St George's University of London, UK) and colleagues identified 12 novel stroke risk loci, but they were unable to confirm these findings in a further 13,347 stroke patients and 29,083 controls.

Amouyel highlights the fact that only 51% the patients in METASTROKE had a stroke subtype assigned. He points out that this reduces the statistical power not only of genetic studies, but also of clinical trials, in which the effect of a drug in patients with one stroke subtype may be diluted by its lack of effect in those with undetermined etiologies.

"Thus, in our clinical practice, it is essential to obtain as much information as possible to classify our patients in the correct subtypes," says Amouyel. "If METASTROKE and other initiatives continue their tireless hunt to characterise genetic susceptibility to stroke, in the near future their genomic results should help us to better classify our patients and to offer them a chance to access the most appropriate treatment."

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